Preparation method of intermediate of anticancer drug gemcitabine

一种药吉、体式的技术，应用在药学领域，能够解决安全隐患、设备腐蚀性、DNA破坏性等问题，达到操作方便、环境友好、工艺安全绿色的效果

Inactive Publication Date: 2016-06-22
陈欣
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Not only there are certain safety hazards in operation, but also there is serious corrosion to the equipment.
Although Chinese patent 201110334019.6 uses a tetrahydropyran ring to protect the two hydroxyl groups on the glycosyl of the gemcitabine intermediate, p-toluenesulfonic acid is used as a catalyst for the docking reaction between the glycosyl and cytosine, and the residue of p-toluenesulfonic acid can lead to Later alcohol reagents react to generate tosylate, p-toluenesulfonate is a genotoxic impurity that is potentially destructive to DNA, so try to avoid using such substances in the process

Method used

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  • Preparation method of intermediate of anticancer drug gemcitabine
  • Preparation method of intermediate of anticancer drug gemcitabine
  • Preparation method of intermediate of anticancer drug gemcitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of isoamyl alcohol to a 500mL reaction flask, stir, heat to 70-80°C to dissolve the white solid, and transfer it to an insulated dropping funnel.

[0033] Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 0.5g to a 1L three-necked flask Phosphotungstic acid and 100mL isoamyl alcohol were stirred and heated to 128-132°C, and then the cytosine silyl ether protecting group was added dropwise. After 2.5 hours of dropwise addition, the tempe...

Embodiment 2

[0035] Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. The temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of isoamyl alcohol to a 500mL reaction flask, stir, heat to 70-80°C to dissolve the white solid, and transfer it to an insulated dropping funnel.

[0036] Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-benzhydryl-1-methanesulfonate (45g, 0.1mol) and 0.8g to a 1L three-necked flask Phosphomolybdic acid and 100mL isoamyl alcohol were stirred and heated to 128-132°C, then the cytosine silyl ether protecting group was added dropwise, after 3 hours of dropping, the temperature was raised to reflux fo...

Embodiment 3

[0038] Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of n-pentanol to a 500mL reaction flask and stir, heat to 70-80°C to dissolve the white solid and transfer it to an insulated dropping funnel.

[0039] Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 1.0g to a 1L three-necked flask Phosphomolybdic acid and 100mL of n-amyl alcohol were stirred and heated to 128-137°C, then the cytosine silyl ether protecting group was added dropwise, after 2 hours of dropping, the temperature was raise...

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Abstract

The invention relates to a preparation method of an intermediate of an anticancer drug gemcitabine. The preparation method comprises steps as follows: cytosine is taken as a raw material and subjected to a reaction with hexamethyl disilazane, a silyl ether protecting group is generated and is docked with 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-3,5-dibenzoate-1-methanesulfonate, and a final product is obtained after post-processing with hydrochloric acid. According to the method, the technology is simple, the operating condition is more convenient, the generation proportion of required isomers is high, the solvent is environment-friendly, harsh reaction conditions are not needed, and the method is suitable for industrial production.

Description

[0001] Divisional application, original application number 2014103946439, application date 2014.08.13, titled a preparation method of gemcitabine hydrochloride intermediate. technical field [0002] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of a gemcitabine hydrochloride intermediate. Background technique [0003] Gemcitabine is a difluoronucleoside anticancer drug that destroys cell replication. It mainly acts on tumor cells in the DNA synthesis phase, that is, cells in the S phase. Under certain conditions, it can prevent the progression from the G1 phase to the S phase. Its chemical name It is 2'-deoxy-2',2'-difluorocytidine, and its chemical structure is as follows: [0004] [0005] There are many synthetic methods of gemcitabine hydrochloride reported so far, and most of the synthetic routes go through an important intermediate β-1-(2'-deoxy-2',2'-difluoro-3',5'-di-O -Benzoyl-D-ribofuranosyl)-4-aminopyrimidin-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55C07H19/073C07H1/00
Inventor 不公告发明人
Owner 陈欣
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